髓系21三体相关基因变异可预防阿尔茨海默病，这一成果由罗格斯大学江鹏团队经过不懈努力而取得。2025年11月24日出版的《自然—神经科学》杂志发表了这一最新研究成果。

考虑到DS中造血突变的风险增加，小组假设某些变异可能赋予小胶质细胞弹性。小组将髓系DS-linked CSF2RB A455D突变引入来自DS患者和健康供体的人多能干细胞衍生的小胶质细胞中，并在4-10月龄嵌合小鼠中研究其功能。该研究组发现这种突变抑制了响应tau病理的I型干扰素信号，减少了炎症，同时增强了吞噬作用，从而改善了小胶质细胞衰老。表达CSF2RB a455d的小胶质细胞形成独特的保护亚群，并保持神经元功能。重要的是，它们取代了tau暴露后患病的野生型小胶质细胞。这些发现证明了工程人类小胶质细胞可以增强对牛头病的恢复能力，为小胶质细胞替代疗法开辟了道路。

据了解，阿尔茨海默病会导致认知能力逐渐下降，但一些人尽管出现了标志性的病理，但仍能保持弹性。唐氏综合症（最常见的阿尔茨海默病的基因变体）患者中有一小部分人表现出了这种韧性。

附：英文原文

Title: A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease

Author: Jin, Mengmeng, Ma, Ziyuan, Dang, Rui, Zhang, Haiwei, Kim, Rachael, Xue, Haipeng, Pascual, Jesse, Yu, Hanwen, Papetti, Ava V., Liu, Yan, Finkbeiner, Steven, Head, Elizabeth, Liu, Ying, Jiang, Peng

Issue&Volume: 2025-11-24

Abstract: Alzheimer’s disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer’s disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience. Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4–10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence. CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies.

DOI: 10.1038/s41593-025-02117-8

Source: https://www.nature.com/articles/s41593-025-02117-8